This invention relates to the general field of controlling fibrinolysis.
It is well accepted that most mammals, including humans, have mechanisms that prevent blood loss when a vessel is severed or ruptured. One such mechanism includes a complex cascade of events that culminate in the formation of a blood clot plugging the opening in the vessel in short order after the opening occurs. Once formed, the clot may be invaded by fibroblasts and eventually be organized into fibrous tissue that will permanently close the opening in the vessel. Alternatively, the clot can dissolve.
When a clot is formed, a large amount of a euglobulin plasma protein known as plasminogen is incorporated in the clot along with other plasma proteins. Plasminogen is activated by plasminogen activators which convert plasminogen to plasmin, a proteolytic enzyme that digests fibrin threads and other substances in the surrounding blood, causing lysis of the clot. This process is termed fibrinolysis. A particularly important plasminogen activator, known as tissue plasminogen activator (t-PA), has been well studied as therapeutic to treat acute clotting such as occurs with a myocardial infarction.
The balance between clotting and lysis is affected by plasminogen activator inhibitors, particularly an inhibitor known as PAI-1. Expression of PAI-1 involves the renin-angiotensin system. Specifically, angiotensin II, which is formed by the sequential enzymatic cleavage of angiotensinogen, ultimately results in expression of PAI-1. Olsen et al., Proc. Nat'l. Acad. Sci. U.S.A. (1991) 88:1928-1932. Angiotensin II is also a potent vasoconstrictor. An angiotensin II receptor is known, and blood pressure control therapeutics based on inhibiting formation of angiotensin II (e.g., ACE inhibitors) and based on antagonizing angiotensin (e.g., DUP753) are known.